HITs and misses in 100 years of heparin.

Heparin was discovered 100 years ago, and the heparin-induced thrombocytopenia syndrome was described 40 years ago. That the most powerful anticoagulant of the last century can also produce the most extreme prothrombotic diathesis is but one of the paradoxes that surround heparin-induced thrombocytopenia. Standard treatment is alternative anticoagulation. Advances continue to be made regarding pathophysiology, prevention, and treatment. Currently, an epidemic of overdiagnosis threatens the well-being of patients, so efforts to educate clinicians on when and how to make this diagnosis are pressing.

Blood platelet kinetics and platelet transfusion.

The discovery of citrate anticoagulant in the 1920s and the development of plastic packs for blood collection in the 1960s laid the groundwork for platelet transfusion therapy on a scale not previously possible. A major limitation, however, was the finding that platelet concentrates prepared from blood anticoagulated with citrate were unsuitable for transfusion because of platelet clumping. We found that this could be prevented by simply reducing the pH of platelet-rich plasma to about 6.5 prior to centrifugation. We used this approach to characterize platelet kinetics and sites of platelet sequestration in normal and pathologic states and to define the influence of variables such as anticoagulant and ABO incompatibility on post-transfusion platelet recovery. The "acidification" approach enabled much wider use of platelet transfusion therapy until alternative means of producing concentrates suitable for transfusion became available.

Beginner's luck--the first in vivo demonstration of functioning platelets; William Duke, 1910.

Blood platelets remained obscure until the early 20th century although from the 1880 s claims that low numbers were associated with certain types of 'purpura' began to gain favour. This article re-appraises critically, but with due consideration to the limited technology of the times, the first remarkable in vivo demonstration of the effects of platelets demonstrated by the serial 'Bleeding Times' reported by William Duke in 1910, when fresh blood was transfused to two thrombocytopenic people. It also speculates on the possible causes of the thrombocytopenia with which Duke's main patient presented.

The immune thrombocytopenia syndrome: a disorder of diverse pathogenesis and clinical presentation.

This article presents a brief history of immune thrombocytopenia (ITP) from the first clinical description written in 1735, through years of controversy about the nature and causes of what was first known as idiopathic thrombocytopenia purpura, then immune thrombocytopenic purpura, and, finally, ITP. Current understanding of ITP's primary and secondary forms and the effect of diverse defects in immune self tolerance that result in the development of antiplatelet antibodies is described. This overview is followed by a narrative list of other articles in this issue on topics ranging from a comprehensive review of the role of antiplatelet antibodies in platelet destruction and production to a review of classic treatment modalities and newer approaches to initial treatment.

Historical hematology: May-Hegglin anomaly.

May-Hegglin anomaly is a rare autosomal dominant platelet disorder characterized by thrombocytopenia, giant platelets, and unique leukocyte inclusion bodies. This disorder was first described by May, a German physician, in 1909, and was subsequently described by a Swiss physician, Hegglin, in 1945. The pathogenesis of the disorder had been unknown until recently, when mutations in the gene encoding for nonmuscle myosin heavy chain IIA (MYH9) were identified. Unique cytoplasmic inclusion bodies are aggregates of nonmuscle myosin heavy chain IIA, and are only present in granulocytes. It is not yet known why inclusion bodies are not present in platelets, monocytes, and lymphocytes, or how giant platelets are formed. Interestingly, MYH9 is also found to be responsible for several related disorders with macrothrombocytopenia and leukocytes inclusion, including Sebastian, Fechtner, and Epstein syndromes, which feature deafness, nephritis, and/or cataract. Current interest is centered upon the mechanisms by which a single mutation causes a variety of phenotypes.

[From 108 minutes to 438 days and further on... (on the 40th anniversary of Iu. A. Gagarin's flight)]. / Ot 108 minut do 438 sutok i dalee...(k 40-letiiu poleta Iu. A. Gagarina).

The progress of science and technology at the end of the XIXth and first half of the XXth century paved the way to start space exploration by humanity. The flight of Yu. A. Gagarin on April 12, 1961 was one of the history watersheds that had a great many of social implications. Piloted missions to space demonstrated the possibility for humans to adapt to the spaceflight factors which, nonetheless, can provoke various unfavorable reactions, particularly on return to Earth. Step-by-step extension of mission length paralleled enhancement of the methods of monitoring of crew health, life support systems, and development of modalities to maintain crew health and performance. The paper contains brief discussion of data acquired in short- and long-term missions including the 438-d mission of cosmonaut-physician V.V. Polyakov. The final section is devoted to the mainstream problems of future piloted space programs.

Heparin-induced thrombocytopenia: historical review.

Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombosis (HITT), recognized as clinical entities only in the past 30 years, have become a major concern for all who work in the field of thromboembolism, its prevention, and treatment. Studies of the 1930 to 1970 era were primarily devoted to the interaction of heparin with platelets in vivo with no knowledge that such interaction could lead to serious morbidity and mortality in as many as 3-5% of patients receiving the drug. When this was recognized in the 1970s, concerns arose regarding recognition and diagnoses. Clinicians, laboratory investigators, and drug companies entered into many research collaborations. The advent of low molecular weight heparin (LMWH) and heparinoids led to studies of their interaction with the IgG antibody that was identified as the mechanism for heparin-induced thrombocytopenia of the immune type. Newer, more sensitive test systems were developed and applied to studies comparing the new low LMWHs and heparinoids. These studies showed a lower incidence of immune-mediated thrombocytopenia with LMWH. The specificity of the antibody for platelet factor 4-heparin complexes led to the development of new tests in the early 1990s. This was soon followed by experiments with antithrombin drugs such as hirudin and argatroban as replacements for heparin in the HIT-HITT syndrome. Shorter courses of heparin therapy and the use of LMWH in place of heparin had become more standard practice in the 1990s.

Platelet kinetics in autosomal dominant macrothrombocytopenia.

A family with autosomal dominant macrothrombocytopenia is described. Despite severe thrombocytopenia, only a moderate hemorrhagic tendency was observed. Kinetic studies revealed a normal platelet survival, normal megakaryocytic numbers, and normal bone marrow responsiveness. The rate of platelet production was set low, despite moderately impaired hemostasis and thrombocytopenia; it apparently was set to maintain another platelet parameter at an optimal level. Measurements of total circulating platelet mass and platelet surface suggested that the platelet production was set to maintain the platelet surface rather than the platelet mass at a normal value.